PROJECT SUMMARY/ABSTRACT Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation method in which direct current is passed through scalp electrodes. The current flows through the scalp, skull and CSF before creating a weak electric field in the brain and causing membrane polarization in cortical neurons. Over the last 20 years, thousands of studies have highlighted many wide ranging tDCS effects on perceptual, cognitive and motor function. More recently, clinical trials have begun to assess the effectiveness of tDCS in treating mental illnesses such as addiction, depression and schizophrenia. However, in spite of the massive amount of financial and scientific resources directed towards tDCS, there is considerable debate about its effectiveness and reproducibility. Perhaps even more surprisingly, the basic mechanism though which tDCS exerts these effects remains unknown. The aim of this project is to answer this fundamental question by elucidating and understanding the mechanisms driving the reported tDCS effects. In addition to the neuromodulatory effects caused by direct polarization of cortical neurons, tDCS also stimulates cranial and cervical nerves in the scalp that give indirect input to the brain. Potential effects from this indirect tDCS neuromodulatory route have been largely overlooked by the field. This project will combine healthy volunteer and animal experiments to investigate a range of potential tDCS mechanisms. Healthy volunteer?s experiments will use careful controls and pharmacological blockers to probe the potential mechanisms that are driving tDCS effects. Animal electrophysiology experiments will be used to test the validity of and to provide insight into these mechanisms. Given the current issues in the tDCS field, the deeper mechanistic insight provided by this project will be vital in advancing the tDCS field at this critical juncture. The new insight provided by this project will help direct financial and scientific resources towards the development of improved noninvasive neuromodulation therapies, which can then more effectively treat a wide range of neurological and psychiatric disorders.